This proposal describes a two-year mentored training program to provide the applicant with intensive training in the area of T cell responses and HIV-1 immunopathogenesis, thereby advancing the applicant's research skills and expertise to facilitate her development as an independent investigator. The candidate will be mentored by established investigators, Drs. Paul Goepfert and Casey Weaver, recognized leaders in the field of vaccine development for HIV-1 and immunology, respectively. She also has the support of a multidisciplinary advisory committee and will pursue a program of education through didactic coursework, conferences, and seminars. She will engage in a research project examining the role of IL-21 HIV-1-specific T cell responses and how these influence the functional quality of the ensuing CD8 T lymphocyte (CD8-TL) response. Despite efforts to understand the immune mechanisms that regulate containment of HIV-1, the specific qualities of anti-viral CD4+ and CD8+ T cell responses required to achieve durable control of HIV-1 remains largely unknown. In the majority of patients, HIV-1-specific CD8-TL gradually become less functional and persist in an exhausted state, unable to effectively eradicate infected targets. We have previously focused on the quality of the response and have found that polyfunctional CD8-TL, capable of cytokine secretion, proliferation, and degranulation are generated in primary infection and are maintained in HIV-1 controllers. However, it remains ill-defined which factors are responsible for the maintenance of these polyfunctional CD8- TL. Several lines of evidence suggest that the early CD4+ T cell-mediated CD8-TL priming events may be crucial for the programming of vigorous effector and memory CD8-TL responses. Mouse models of chronic viral infection demonstrate a vital role for IL-21, in the induction, quality, and longevity of anti-viral CD8-TL responses. Our preliminary studies demonstrate that HIV-1-specific CD4+ T cells are compromised in their ability to produce IL-21 during chronic infection. Interestingly, we demonstrate that HIV-1-specific CD8-TL are also capable of producing IL-21 and are even better associated with viral control than their CD4+ T cell counterparts. In light of the altered IL-21 production in HIV-1 and its proposed importance in the generation of effective virus-specific effector CD8-TL, we hypothesize that the loss of polyfunctional CD8-TL in chronic HIV-1 infection is a consequence of the functional abrogation of IL-21-producing HIV-1-specific CD4+ and CD8+ T cells. Utilizing polychromatic flow cytometry, this project proposes to elucidate the quantitative and qualitative requirements of the latter cells in contributing to the generation of protective, long-lived HIV-1-specific CD8-TL responses in HIV-1 controllers. Understanding the molecular mechanisms accounting for the link between CD4+ T cell help and CD8+ T cell functional quality and anti-viral efficacy will provide new insights for recapitulation into an effective HIV-1 vaccine.